A randomised-controlled Phase I de-escalation trial of Molnupiravir and Nirmatrelvir/Ritonavir combination for mild-moderate SARS-CoV-2 infection

Khoo et al., medRxiv, doi:10.1101/2025.05.01.25326797, AGILE CST-8, NCT04746183, May 2025

https://c19early.org/khoo3pl.html

Randomized open-label phase I trial of 24 outpatients with mild-moderate COVID-19 showing safety and tolerability of combined molnupiravir and paxlovid therapy. The paper reports that the control group received standard of care and "no participant in the standard of care arm received any antiviral therapy", the CONSORT diagram indicates the control group received placebo, and the supplementary data indicates the control group received paxlovid. Authors report faster initial viral clearance with treatment using a bi-exponential model, although this did not reach significance without the assumption that treatment effects only the "fast" phase and not the "persistent" phase, and results are limited with the small sample size and baseline differences. Supplemental Table 2 shows greater decline of viral load in the control group for days 2-5.

Standard of Care (SOC) for COVID-19 in the study country, the United Kingdom, is very poor with very low average efficacy for approved treatments1. The United Kingdom focused on expensive high-profit treatments, approving only one low-cost treatment, which required a prescription and had limited adoption. The high-cost prescription treatment strategy reduces the probability of treatment—especially early—due to access and cost barriers, and eliminates complementary and synergistic benefits seen with many low-cost treatments.

Important missing comments or errors? Let us know.

Study covers molnupiravir and paxlovid.

viral load, 1.4% higher, relative load 1.01, p = 0.94, treatment mean 4.97 (±1.72) n=16, control mean 5.04 (±2.8) n=8, relative reduction in viral load, day 5.

viral load, 12.5% higher, relative load 1.12, p = 0.61, treatment mean 4.24 (±2.28) n=16, control mean 4.77 (±2.59) n=8, relative reduction in viral load, day 4.

viral load, 31.0% higher, relative load 1.31, p = 0.34, treatment mean 3.23 (±2.32) n=16, control mean 4.23 (±2.4) n=8, relative reduction in viral load, day 3.

viral load, 26.7% higher, relative load 1.27, p = 0.50, treatment mean 1.95 (±1.59) n=16, control mean 2.47 (±2.01) n=8, relative reduction in viral load, day 2.

risk of no viral clearance, 16.7% lower, RR 0.83, p = 1.00, treatment 5 of 16 (31.2%), control 3 of 8 (37.5%), NNT 16, day 5 and 11 viral clearance.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. c19early.org, c19early.org/soc/united-kingdom.html.c19early.org/soc/united-kingdom.html.

Khoo et al., 2 May 2025, Randomized Controlled Trial, United Kingdom, preprint, 31 authors, study period January 2023 - September 2023, this trial uses multiple treatments in the treatment arm (combined with molnupiravir) - results of individual treatments may vary, trial NCT04746183 (history) (AGILE CST-8). Contact: khoo@liverpool.ac.uk.

This Paper Paxlovid All

A randomised-controlled Phase I de-escalation trial of Molnupiravir and Nirmatrelvir/Ritonavir combination for mild-moderate SARS-CoV-2 infection

Saye H Khoo, Prof Richard Fitzgerald, Christopher J Edwards, Shazaad Ahmad, Geoffrey Saunders, Laura J Else, Victoria Shaw, PhD Pavel Mozgunov, MSc Josh Northey, PhD Laura Dickinson, PhD Emma Knox, Amanda Buadi, PhD Colin Hale, Helen E Reynolds, Calley Middleton, MSc Katie Bullock, Prof Lauren Walker, Michelle Tetlow, Rebecca Lyon, Jennifer Gibney, Alieu Amara, Prof William Greenhalf, Prof Abigail Burdon, Jan Dixon, Prof Thomas Jaki, Justin Chiong, David G Lalloo, Andrew Owen, Michael Jacobs, PhD Thomas Fletcher, PhD Gareth Griffiths

doi:10.1101/2025.05.01.25326797

Background The AGILE CST-8 (NCT04746183) Phase I de-escalation trial evaluated the safety and tolerability of combination molnupiravir and nirmatrelvir/ritonavir for mild-moderate COVID-19. Methods Adult out-patients with SARS-CoV-2 infection within five days of symptoms were randomly assigned 2:1 to receive molnupiravir (starting at 800mg twice daily (BD) reducing to 600mg and 400mg if necessary) in combination with nirmatrelvir (300mg)/ritonavir (100mg) BD for 5 days versus Standard of care. Using a dose de-escalation, open-label, Bayesian adaptive Phase I trial a combination dose was considered unsafe if the probability of 30% or greater dose-limiting toxicity risk (DLT -the primary outcome) over standard of care was 25% or higher. Secondary endpoints included tolerability, clinical progression, pharmacokinetics and virological responses. Findings Of 49 participants screened, 24 were enrolled (16 combination, 8 standard of care) between January 2023 and September 2023. For the primary endpoint, to day 11, no participant starting molnupiravir at 800mg (BD) in combination with nirmatrelvir/ritonavir reported a DLT by day 11 (primary endpoint) or by day 29; dose de-escalation was not required. No participants reported severe adverse events (grade>=3). Although proportion of swab PCR negativity at day 5 and day 11 were not statistically different, faster initial viral clearance was observed with treatment. Penetration of nirmatrelvir into saliva, nasal secretions and tears was 19%, 65% and 91% that of plasma. Interpretation Molnupiravir in combination with nirmatrelvir/ritonavir was safe and well-tolerated; later phase trials should evaluate combination therapy at currently recommended doses for each drug.

Contributors SHK, GG, RF, TF, TJ, PM, LW contributed to study design. SHK, GG, GS, JN contributed to data analysis and interpretation. RF, SA, CJE led clinical conduct as principal investigators of the clinical sites. RL, RF, LW, CJE, SA, AB participated in clinical assessment and data collection. LJE, LD, VS, WG, CH, KB, AA contributed to study bioanalysis. EK, HER, MT, CM, JD, JG, JC contributed to study management and execution. DGL, AO, MJ contributed to the design of the AGILE platform. The manuscript was written by the authors, with SHK and GG as the overall lead authors. No one who is not an author contributed to writing the manuscript. All authors had full access to the data and GS and JN directly accessed and verified the underlying data reported in the manuscript. The authors assume responsibility for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. Blood and lymphatic system disorders Ear and labyrinth disorders 0 (0 General disorders and administration site conditions Infections and infestations 0 (0•0%) Musculoskeletal and connective tissue disorders Renal and urinary disorders 0 (0 Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders

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DOI record: { "DOI": "10.1101/2025.05.01.25326797", "URL": "http://dx.doi.org/10.1101/2025.05.01.25326797", "abstract": "Background The AGILE CST-8 (NCT04746183) Phase I de-escalation trial evaluated the safety and tolerability of combination molnupiravir and nirmatrelvir/ritonavir for mild-moderate COVID-19. Methods Adult out-patients with SARS-CoV-2 infection within five days of symptoms were randomly assigned 2:1 to receive molnupiravir (starting at 800mg twice daily (BD) reducing to 600mg and 400mg if necessary) in combination with nirmatrelvir (300mg)/ritonavir (100mg) BD for 5 days versus Standard of care. Using a dose de-escalation, open-label, Bayesian adaptive Phase I trial a combination dose was considered unsafe if the probability of 30% or greater dose-limiting toxicity risk (DLT - the primary outcome) over standard of care was 25% or higher. Secondary endpoints included tolerability, clinical progression, pharmacokinetics and virological responses. Findings Of 49 participants screened, 24 were enrolled (16 combination, 8 standard of care) between January 2023 and September 2023. For the primary endpoint, to day 11, no participant starting molnupiravir at 800mg (BD) in combination with nirmatrelvir/ritonavir reported a DLT by day 11 (primary endpoint) or by day 29; dose de-escalation was not required. No participants reported severe adverse events (grade>=3). Although proportion of swab PCR negativity at day 5 and day 11 were not statistically different, faster initial viral clearance was observed with treatment. Penetration of nirmatrelvir into saliva, nasal secretions and tears was 19%, 65% and 91% that of plasma. Interpretation Molnupiravir in combination with nirmatrelvir/ritonavir was safe and well-tolerated; later phase trials should evaluate combination therapy at currently recommended doses for each drug. 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